The epidermal growth factor receptor (EGFR) is known to have four receptor subtypes, i.e., EGFR/ErbB1, Her-2/ErbB2, Her-3/ErbB3, and Her-4/ErbB4. They are abnormally overexpressed in most solid tumor cells. Also, activation of the receptor by ligands leads to activation of the cellular signaling pathway, which gives rise to growth, differentiation, angiogenesis, metastasis, and resistance of tumor cells (A. Wells, Int. J. Biochem. Cell Biol., 1999, 31, 637-643). Therefore, it is expected that blocking of the tumor cell signaling pathway mediated by the epidermal growth factor receptor would produce antitumor effects. Hence, there have been many research efforts for developing anticancer drugs targeting the epidermal growth factor receptor.
Such anticancer drugs targeting the epidermal growth factor receptor are categorized into two groups: monoclonal antibodies targeting an extracellular domain and small molecule drugs targeting an intracellular tyrosine kinase. The monoclonal antibodies have an advantage of a good pharmaceutical efficacy with a less extent of side effects due to its selective binding on the epidermal growth factor receptors. However, the monoclonal antibodies have drawbacks that they are quite expensive and must be administered by injection. Meanwhile, the small molecule drugs targeting a tyrosine kinase are relatively inexpensive and orally administrable, and they also have a good pharmaceutical efficacy through reacting with the receptor subtypes (e.g., EGFR, Her-2, Her-3 and Her-4) selectively or simultaneously.
Examples of the small molecule drugs include selective inhibitors of EGFR such as Iressa® (Gefitinib, AstraZenaca) and Tarceva® (Erlotinib, Roche), and dual inhibitors simultaneously blocking EGFR and Her-2 such as Tykerb® (Lapatinib, GlaxoSmithKline). These drugs are currently being used for treating lung cancer and advanced Her-2 positive breast cancer, respectively. Clinical trials therefor are also being conducted to increase the efficacy against other solid tumors.
A recent study has reported that a second mutation—i.e., a threonine-to-methionine substitution at the amino acid position 790 in adenosine triphosphate (ATP)-binding sites to the EGFR tyrosin kinase domain—can reduce the binding ability of the drug, which results in a drastic decrease in the drug response rate (C. H. Gow, et al., PLoS Med., 2005, 2(9), e269). Thus, it is required to develop a drug having enhanced inhibitory activities against EGFR resistant cancer cells.
Korean Patent Laid-open Publication No. 2008-0107294 discloses a compound of formula (I), which selectively and effectively inhibits the growth of cancer cells and the development of drug resistance induced by the EGFR and its mutants without side effects. However, it has been found that the pharmaceutical formulation comprising the compound of formula (I) as an active ingredient and its pharmaceutically acceptable additives facilitates the formation of a compound of formula (II) (hereinafter, referred to as the related compound IV) under certain storage conditions, thereby reducing the amount of the compound of formula (I).

The purity of an active ingredient is an important factor for preparing a safe and effective pharmaceutical composition because certain impurities contained in a drug substance may produce side effects during treatment. Some of the impurities can be removed during the preparation of the drug. But certain materials produced by degradation of the drug due to the changes in such various conditions as temperature, humidity and light may remain as impurities.
The present inventors have endeavored to study the factors that promote the formation of the related compound IV during storage of a pharmaceutical formulation comprising a compound of formula (I) and have found that pharmaceutically acceptable additives, particularly metallic salts contained in lubricants, cause expedition of the formation of the related compound IV. Hence, the present inventors have developed a pharmaceutical composition having an enhanced stability by employing a non-metallic salt lubricant, which is free of a metallic salt component.